# Trigeminal nerve stimulation to modulate cortical spreading depolarizations after brain injury

> **NIH NIH R21** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2020 · $209,375

## Abstract

Project Summary
Cortical spreading depolarization (CSD) is a phenomenon of depressed electrical activity in the brain that has
been clinically associated with a variety of acute brain injuries, including 100% of patients with malignant
hemispheric ischemic stroke. In addition to being a real-time marker of brain damage, CSDs are also believed
to be a mechanism of secondary injury in the compromised tissue of acute brain injuries. Accumulating
evidence proves that the expansion of ischemic territory is closely coupled to the occurrence of CSDs, due to
the increased metabolic demand of repolarization (oxygen depletion associated with vasoconstriction). Thus,
recent studies have focused on the use of various drugs to create complete cessation of CSDs in the injured
brain as a method of preventing further tissue loss. However, these pharmacological approaches are
systemic and typically have significant side effects. Therefore, new strategies are needed to selectively
reduce the deleterious consequences of CSDs. Whether or not injury occurs after CSDs depends greatly on
the capacity of tissues to re-establish ionic gradients in the aftermath of CSDs. This capacity is influenced
mainly by the availability of ATP and the ability of a brain region to profoundly increase cerebral blood flow
(CBF) to match the energy demands. The trigeminal nerve is the largest cranial nerve forming an extensive
network throughout the central nervous system (CNS), and is unique because of its intimate connection with
the cerebral and meningeal blood vessels, referred to as the trigemino-cerebrovascular system. It is also
capable of activating the diving reflex, whose primary role is to conserve oxygen for sensitive brain and heart
tissue. We have previously shown that electrical stimulation of the trigeminal nerve (TNS) not only increases
CBF but also significantly increases brain oxygen tension in the brains of normal, traumatic brain injury, and
hemorrhagic shock rats. Additionally, in our preliminary studies, TNS treatment in normal brains increased
the threshold current required for eliciting CSD and slowed its propagation velocity. Furthermore, TNS
treatment immediately before middle cerebral artery occlusion (MCAO) in rats decreased infarction volumes,
and the numbers of CSDs. We therefore hypothesize that TNS can reduce the detrimental consequences of
CSDs in the injured brain by initiating cerebral vasodilation and increasing energy substrate levels for quicker
repolarization. In this proposal, we aim to: (1) Investigate the effects of TNS on the release of cerebral
vasodilators and energy substrates in the normal brain; (2) Explore the effects of TNS in obtaining the ideal
amount of cerebral vasodilators and energy substrates to reduce injury development after CSDs. The
proposed study would be the first ever research to reduce deleterious consequences of CSDs on the basis
of precision medicine for the injured brain. The information obtained from these studies will...

## Key facts

- **NIH application ID:** 9877685
- **Project number:** 1R21NS114763-01
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Chunyan Li
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $209,375
- **Award type:** 1
- **Project period:** 2019-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9877685

## Citation

> US National Institutes of Health, RePORTER application 9877685, Trigeminal nerve stimulation to modulate cortical spreading depolarizations after brain injury (1R21NS114763-01). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9877685. Licensed CC0.

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